Percorrer por autor "Castanho, Miguel A. R. B."
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- Development of synthetic light-chain antibodies as novel and potent HIV fusion inhibitorsPublication . Cunha-Santos, Catarina; Figueira, Tiago N.; Borrego, Pedro; Oliveira, Soraia S.; Rocha, Cheila; Couto, Andreia; Cantante, Cátia; Santos- Costa, Quirina; Azevedo-Pereira, José M.; Fontes, Carlos M. G. A.; Taveira, Nuno; Aires-Da-Silva, Frederico; Castanho, Miguel A. R. B.; Veiga, Ana Salomé; Gonçalves, João"Objective: To develop a novel and potent fusion inhibitor of HIV infection based on a rational strategy for synthetic antibody library construction. Design: The reduced molecular weight of single-domain antibodies (sdAbs) allows targeting of cryptic epitopes, the most conserved and critical ones in the context of HIV entry. Heavy-chain sdAbs from camelids are particularly suited for this type of epitope recognition because of the presence of long and flexible antigen-binding regions [complementary-determining regions (CDRs)]."
- Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor ActivationPublication . Diógenes, Maria José; Dias, Raquel B.; Rombo, Diogo M.; Miranda, Hugo Vicente; Maiolino, Francesca; Guerreiro, Patrícia; Näsström, Thomas; Franquelim, Henri G.; Oliveira, Luis M. A.; Castanho, Miguel A. R. B.; Lannfelt, Lars; Bergström, Joakim; Ingelsson, Martin; Quintas, Alexandre; Sebastião, Ana M.; Lopes, Luísa V.; Outeiro, Tiago FlemingParkinson’s disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of -synuclein (a-syn) in various brain regions is themajorpathological hallmark. Indeed, themotorsymptomsinPDare causedby a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation onAMPAandNMDAreceptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposuretoa-synoligomersdrivestheincreaseofglutamatergicsynaptictransmission,preventingfurtherpotentiationbyphysiologicalstimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.